Background: Modulation of inflammation and oxidative stress appears to limit sepsis-induced damage in experimental models. The kidney is one of the most sensitive organs to injury during septic shock. In this study, we evaluated the effect of N-acetylcysteine (NAC) administration in conjunction with fluid resuscitation on renal oxygenation and function. We hypothesized that reducing inflammation would improve the microcirculatory oxygenation in the kidney and limit the onset of acute kidney injury (AKI).

Methods: Rats were randomized into five groups (n&thinsp;=&thinsp;8 per group): (1) control group, (2) control&thinsp;+&thinsp;NAC, (3) endotoxemic shock with lipopolysaccharide (LPS) without fluids, (4) LPS&thinsp;+&thinsp;fluid resuscitation, and (5) LPS&thinsp;+&thinsp;fluid resuscitation&thinsp;+&thinsp;NAC (150&nbsp;mg/kg/h). Fluid resuscitation was initiated at 120&nbsp;min and maintained at fixed volume for 2&nbsp;h with hydroxyethyl starch (HES 130/0.4) dissolved in acetate-balanced Ringer&rsquo;s solution (Volulyte) with or without supplementation with NAC (150&nbsp;mg/kg/h). Oxygen tension in the renal cortex (C&mu;PO2), outer medulla (M&mu;PO2), and renal vein was measured using phosphorimetry. Biomarkers of renal injury, inflammation, and oxidative stress were assessed in kidney tissues.

Conclusion: The addition of NAC to fluid resuscitation may improve renal oxygenation and attenuate microvascular dysfunction and AKI. Decreases in renal NO and hyaluronic acid levels may be involved in this beneficial effect. A therapeutic strategy combining initial fluid resuscitation with antioxidant therapies may prevent sepsis-induced AKI.

Mentions:
After a 30-min stabilization, the rats were randomized into the five following groups at baseline: (1) control group, (2) control + NAC, (3) endotoxemic shock with lipopolysaccharide (LPS) without fluid resuscitation, (4) LPS + fluid resuscitation, and (5) LPS + fluid resuscitation + NAC (150 mg/kg/h). The groups received either an intravenous bolus of 5 mg/kg LPS (LPS group; Escherichia coli 0127:B8, Sigma, Paris, France; three groups of eight rats each) or vehicle (control group, two groups of eight rats each). Animals were observed or kept in shock for over 120 min. Fluid resuscitation (15 ml/kg/h) was then started and maintained for 180 min in the LPS groups with 6 % hydroxyethyl starch (HES130/0.4) dissolved in Ringer’s acetate (HES-RA; Volulyte® 6 %, Fresenius Kabi Deutschland GmbH, Germany) as a balanced colloid solution. NAC was administered to the appropriate groups at a rate of 150 mg/kg/h as previously reported [15]. An LPS group was not resuscitated to serve as a shock control. Time points for the measurements were baseline (T0), during shock 120 min after administration of LPS (T1), 30 min after initiating fluid resuscitation (early reperfusion phase) (T2), and 120 min after starting fluid resuscitation (late reperfusion phase) (T3), which was the final endpoint of the experiment (Fig. 1).Fig. 1

Mentions:
After a 30-min stabilization, the rats were randomized into the five following groups at baseline: (1) control group, (2) control + NAC, (3) endotoxemic shock with lipopolysaccharide (LPS) without fluid resuscitation, (4) LPS + fluid resuscitation, and (5) LPS + fluid resuscitation + NAC (150 mg/kg/h). The groups received either an intravenous bolus of 5 mg/kg LPS (LPS group; Escherichia coli 0127:B8, Sigma, Paris, France; three groups of eight rats each) or vehicle (control group, two groups of eight rats each). Animals were observed or kept in shock for over 120 min. Fluid resuscitation (15 ml/kg/h) was then started and maintained for 180 min in the LPS groups with 6 % hydroxyethyl starch (HES130/0.4) dissolved in Ringer’s acetate (HES-RA; Volulyte® 6 %, Fresenius Kabi Deutschland GmbH, Germany) as a balanced colloid solution. NAC was administered to the appropriate groups at a rate of 150 mg/kg/h as previously reported [15]. An LPS group was not resuscitated to serve as a shock control. Time points for the measurements were baseline (T0), during shock 120 min after administration of LPS (T1), 30 min after initiating fluid resuscitation (early reperfusion phase) (T2), and 120 min after starting fluid resuscitation (late reperfusion phase) (T3), which was the final endpoint of the experiment (Fig. 1).Fig. 1

Background: Modulation of inflammation and oxidative stress appears to limit sepsis-induced damage in experimental models. The kidney is one of the most sensitive organs to injury during septic shock. In this study, we evaluated the effect of N-acetylcysteine (NAC) administration in conjunction with fluid resuscitation on renal oxygenation and function. We hypothesized that reducing inflammation would improve the microcirculatory oxygenation in the kidney and limit the onset of acute kidney injury (AKI).

Methods: Rats were randomized into five groups (n&thinsp;=&thinsp;8 per group): (1) control group, (2) control&thinsp;+&thinsp;NAC, (3) endotoxemic shock with lipopolysaccharide (LPS) without fluids, (4) LPS&thinsp;+&thinsp;fluid resuscitation, and (5) LPS&thinsp;+&thinsp;fluid resuscitation&thinsp;+&thinsp;NAC (150&nbsp;mg/kg/h). Fluid resuscitation was initiated at 120&nbsp;min and maintained at fixed volume for 2&nbsp;h with hydroxyethyl starch (HES 130/0.4) dissolved in acetate-balanced Ringer&rsquo;s solution (Volulyte) with or without supplementation with NAC (150&nbsp;mg/kg/h). Oxygen tension in the renal cortex (C&mu;PO2), outer medulla (M&mu;PO2), and renal vein was measured using phosphorimetry. Biomarkers of renal injury, inflammation, and oxidative stress were assessed in kidney tissues.

Conclusion: The addition of NAC to fluid resuscitation may improve renal oxygenation and attenuate microvascular dysfunction and AKI. Decreases in renal NO and hyaluronic acid levels may be involved in this beneficial effect. A therapeutic strategy combining initial fluid resuscitation with antioxidant therapies may prevent sepsis-induced AKI.